Androgen Mediated Regulation of the G1-S Transition in Prostate Cancer

Knudsen, Karen E.; Fribourg, Anne F.; Petre, Christin E.; Wetherill, Yelena B.

doi:10.1007/978-1-4615-0965-3_6

Cited by 4 publications

(6 citation statements)

References 69 publications

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“…In stably transfected LNCaP cells, we found exogenous FUS expression significantly inhibits cell growth, causes G 1 arrest and promotes apoptosis. The AR is known to regulate factors important in cell-cycle progression and appears be particularly important in G 1 /S progression because androgen depletion results in G 1 arrest (24). In agreement with this we also found LNCaP cells to arrest in G 1 following removal of androgen, whereas addition of androgen resulted in an increase in the number of cells progressing to S and G 2 /M.…”

Section: Discussionsupporting

confidence: 89%

“…and a decrease in p27 promote G 1 transition (22)(23)(24). Our observed reduction in the expression of this cyclin and the increase in p27 following exogenous expression of FUS suggests that FUS induces G 1 arrest and thus affects androgen-dependent proliferation, at least in part, via modulation of these factors.…”

Section: Discussionmentioning

confidence: 67%

“…This data therefore fits with the mechanism of regulation proposed by Wang and colleagues (12) and suggests that androgen withdrawalmediated repression of cyclin D1 expression is via alterations in recruitment of FUS to the CCND1 promoter. It thus appears that cyclin D1 is a target of both androgens (22)(23)(24) and FUS (12; and data herein). We have shown that FUS levels are regulated by androgens, and others have shown that cyclin D1 itself is a corepressor of the androgen receptor (26).…”

Section: Discussionmentioning

confidence: 86%

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FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth

et al. 2011

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Progression of prostate cancer is highly dependent upon the androgen receptor pathway, such that knowledge of androgen-regulated proteins is vital to understand and combat this disease. Using a proteomic screen, we found the RNA-binding protein FUS/TLS (Fused in Ewing's Sarcoma/Translocated in Liposarcoma) to be downregulated in response to androgen. FUS has recently been shown to be recruited by noncoding RNAs to the regulatory regions of target genes such as cyclin D1, in which it represses transcription by disrupting complex formation. Here we show that FUS has some characteristics of a putative tumor suppressor, as its overexpression promoted growth inhibition and apoptosis of prostate cancer cells, whereas its knockdown increased cell proliferation. This effect was reproducible in vivo, such that increasing FUS levels in tumor xenografts led to dramatic tumor regression. Furthermore, FUS promoted conditions that favored cell-cycle arrest by reducing the levels of proliferative factors such as cyclin D1 and Cdk6 and by increasing levels of the antiproliferative Cdk inhibitor p27. Immunohistochemical analysis revealed that FUS expression is inversely correlated with Gleason grade, demonstrating that patients with high levels of FUS survived longer and were less likely to have bone metastases, suggesting that loss of FUS expression may contribute to cancer progression. Taken together, our results address the question of how androgens regulate cell-cycle progression, by demonstrating that FUS is a key link between androgen receptor signaling and cell-cycle progression in prostate cancer.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 86%

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FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth

et al. 2011

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“…It has been shown that AR played an important role in regulating regulatory factors in development of the cell cycle, especially in development of G1 / S, since androgen depletion can inhibit G1 (29). According to these fi ndings, Brooke et al (26) reported that in LNCaP cells followed the elimination of androgens, prevented from entering the G1 phase, while the addition of androgen led to an increase in number of progressive cells to S and G2 / M phases.…”

Section: Gene and Cancer Correlationmechanism And Review Of Researchmentioning

confidence: 99%

Structure and function of FUS gene in prostate cancer

Ghanbarpanah¹,

Kohanpour²,

Hosseini-Beheshti³

et al. 2018

BLL

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BACKGROUND: FUS reduces the proliferator factors such as cyclin D1 and Cdk6, and increases Cdk and p27. Therefore, FUS prevents the growth of prostate cancer cells. METHODS: This review tried to summarize data about FUS gene expression in correlation with the degree of prostate cancer. To fi nd the relevant studies, the search in PubMed, Science Direct, and Scopus were performed. RESULTS: Increasing the expression of FUS decreases and increases the rate of apoptosis of prostate cancer cells, respectively. In fact, FUS reduces the proliferator factors such as: cyclin D1 and Cdk6, and increases Cdk (an anti-proliferation factor) and p27 (a proliferative inhibitory factor). Therefore, FUS prevents the growth of prostate cancer cells. An immuno-histochemical analysis showed that FUS gene expression had an inverse correlation with the degree of prostate cancer, which suggests that patients with higher levels of FUS are more likely to survive and less likely to have bone pain. CONCLUSION: The key to FUS is the signaling of the androgen receptor and the progression of the cell cycle in prostate cancer. Based on these fi ndings, we might be able to consider exogenous expression of FUS as a treatment for prostate cancer (Fig. 1, Ref. 32).

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“…The hsp70-1 expression level is elevated by 65% in G2/M phase of the cell cycle and is lowest in G1 phase among G1, S, and G2/M2 phases of the cell cycle (34). Cultivation of LNCaP cells under androgen-deprived conditions arrests cells at G1 phase of the cell cycle (35). Similarly, treatment with the classical antiandrogens Bic and Flut, and DL3 induce G1 arrest in LNCaP cells (data not shown).…”

Section: Discussionmentioning

confidence: 83%

Regulation of heat shock protein 70-1 expression by androgen receptor and its signaling in human prostate cancer cells

Tan²,

Wortman³

et al. 2009

Int J Oncol

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Abstract. Heat shock protein (hsp) 70-1 (hsp70-1) is overexpressed in human prostate cancer cells and may play important roles in prostate cancer resistance to conventional therapies. The purpose of this study was to investigate whether androgen receptor (AR) and its signaling regulate hsp70-1 expression. Several lines of AR-positive (LNCaP, LAPC-4, and 22Rv1) and -negative (PC-3, DU145, WPE1-NB14 and WPE1-NB-26) human prostatic cells were used in the study. Dihydrotestosterone (DHT) enhanced hsp70-1 expression in LNCaP cells. Expression of hsp70-1 in LNCaP cells was downregulated by the anti-androgens bicalutamide (Bic), and flutamide (Flut), and a newly identified AR signaling antagonist DL3. The downregulation of hsp70-1 by DL3 was also observed in LAPC-4 and 22Rv1 cells, but not in the four lines of AR-negative cells examined. Expression of hsp70-1 was also reduced by DL3 in PC-3 cells engineered with AR. On the other hand, knocking down AR in LNCaP cells by siRNA moderately reduced hsp70-1 level and abolished effects of DL3 on hsp70-1 expression. DL3 reduced hsp70-1 mRNA synthesis in cells and its in vitro gene transcription but did not significantly alter the stabilities of hsp70-1 mRNA and protein. Chromatin-immunoprecipitation (ChIP) assay showed that AR bound to the promoter region of HSPA1B gene, which was reduced in cells treated with DL3 or Bic. These data suggest that AR and its signaling regulate hsp70-1 expression in prostate cancer cells and that HSPA1B could be an AR target gene.

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Androgen Mediated Regulation of the G1-S Transition in Prostate Cancer

Cited by 4 publications

References 69 publications

FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth

FUS/TLS Is a Novel Mediator of Androgen-Dependent Cell-Cycle Progression and Prostate Cancer Growth

Structure and function of FUS gene in prostate cancer

Regulation of heat shock protein 70-1 expression by androgen receptor and its signaling in human prostate cancer cells

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